The objective of this proposal is to develop a fully integrated nanoliter droplet (nanodroplet)-based electrowetting (EW) device to accelerate the drug discovery process, in particular the field of adsorption, distribution, metabolism, excretion, and toxicology (ADMET). Traditionally, drug discovery has been a sequential process from therapeutic target identification/validation to primary screening for initial (lead) chemical compounds to chemical optimization for potency. These steps are followed by ADMET evaluation, pre-clinical/clinical trials, manufacturing and marketing. Recent data suggests 80% of all potential drugs are eliminated from the pipeline due to poor ADMET properties. This observation has caused a dramatic change in the process. The biopharmaceutical industry is now searching for technologies that will enable the simultaneous screening of chemical compounds for optimal therapeutic potency and the most favorable ADMET properties. By promoting only chemical leads that possess this combination of appropriate "drug- like" characteristics, it is predicted that the pharmaceutical development will realize a dramatic cost savings and accelerate the overall drug development process. In Phase I, we intend to demonstrate the applicability of EW to various ADMET methodologies. Several simple biochemical assays have already been demonstrated on our platform. However, for ADMET, more complex systems are often employed. Therefore, our studies will demonstrate the ability to perform microsomal cytochrome P-450 assays, adherent and non-adherent cell-based assays, and quantitative polymerase chain reaction. This family of protocols will serve an experimental foundation for the integration of a large suite of ADMET assays in Phase II. The biochemical versatility of the EW platform is attractive, as are several other features of EW. By utilizing only nanodroplets, each assay requires ~1,000 times less reagents compared to current methods. Thus, precious chemical compounds, target proteins, and cell lines used in the drug screening process are conserved. In addition, EW facilitates the rapid execution of multiple assay protocols concurrently. So, in Phase II we anticipate a single chip generating greater than 100,000 data points/day. This represents a dramatic increase in through-put versus the industry screening standard. Consequently, the Nanolytics' EW platform is uniquely positioned to help facilitate the acceleration of the drug discovery process. Nanolytics will design and commercialize an instrument that uses extremely small volumes to facilitate the development of effective and safe therapeutic drugs. Based on current data, implementation of this kind of instrument would represent the single largest cost savings opportunity for biopharmaceutical companies.
Thesaurus Terms: bioassay, cheminformatics, experimental design, method development, nanotechnology, technology /technique development adsorption, excretion, metabolism, molecular dynamics, molecular probe, small molecule, toxicology biotechnology, microcapsule, microfluidics, polymerase chain reaction
